How can I be sure that the patient has acute porphyrias?

Porphyrias are a group of nine metabolic disorders associated with enzymatic defects of heme biosynthesis, which may lead to overexcretion of porphyrins or their precursors (ALA and PBG) in urine or feces (Table I). All are in-born errors of metabolism, except for porphyria cutanea tarda, which is mostly acquired. With the exception of X-linked protoporphyria (X-EPP), all are due to enzymatic deficiencies of heme synthesis.

Table I. Types, classifications, and features of porphyrias

Classifications of porphyria

Type of porphyria

Enzyme defect

Chromosomal locus

Approximate gene length (kb)

Exons

Inheritance

Hepatic

Erythropoietic

Acute

Chronic

Cutaneous

ADP

ALAD/PBGS

9q34

16

12

AR

?X

X

AIP

PBGD/HMBS

11q24

10

15

AD

X

X

VP

PPOX

1q22-23

4.8-5.5

13

AD

X

X

X

HCP

CPOX

3q12

14

7

AD

X

X

6

X

PCT

UROD

1p34

10

10

AD in familial type

X

X

X

HEP

UROD

1p34

10

10

AR

X

X

X

X

CEP

UROS

10q25.3-q26.3

40

10

AR

X

X

X

EPP

FECH

18q21.3

45

11

AR*

X

X

X

X-EPP

ALAS2

Xp11.21

22

11

XL

X

X

X

Porphyrias are usually classified based either on the predominant site of overproducution of heme precursors (hepatic vs. erythroid) or on the predominant clinical manifestation (acute vs. cutaneous). There are six hepatic porphyrias, namely, acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), ALA dehydratase deficiency porphyria (ADP), porphyria cutanea tarda (PCT), and hepatoerythropoietic porphyria (HEP). Erythropoeitic porphyrias, on the other hand, may also include HEP, along with congenital erythropoietic porphyria (CEP) and erythropoietic protoporphyria (EPP) .

Of the six hepatic porphyrias, four are considered "acute" because they may present with sudden attacks of clinically indistinguishable neurologic manifestations. The acute porphyrias are AIP, VP, HCP, and ADP. With the exception of ADP, all acute porphyrias are inherited in an autosomal dominant fashion and are of low penetrance. Furthermore, VP and HCP may also present with skin lesions similar to cutaneous porphyrias. Variegate porphyria presents with cutaneous manifestations about 60% of the time; hereditary coproporphyria does so only rarely (~5%).

The remaining porphyrias, including PCT, HEP, EPP, and CEP, predominantly present with cutaneous manifestations and are classified as chronic porphyrias. Cutaneous porphyrias, in turn, may be divided into hepatic and erythropoietic types. PCT is considered a prototypic chronic hepatic porphyria, whereas HEP may be classified in both categories. EPP and CEP, on the other hand, are considered erythropoietic porphyrias because, in them, the overproduction of porphyrins is limited to developing red blood cells (RBCs). However, in EPP secondary liver disease (hepatic fibrosis or cirrhosis) due to protoporphyrin, accumulation may develop.

Heme synthesis and regulation

In eukaryotes, the first and last three steps of the pathway are located in the mitochondria while the remainder occurs in the cytoplasm. In addition, the initial three enzymes of the pathway (ALAS, ALAD/PBGS, and PBGD/HMBS) are synthesized in two isoforms: one found ubiquitously and one found only in erythroid precursors. Regardless of the catalyst involved, biosynthesis of all tetrapyrroles begins with the synthesis of 5-aminolevulinic acid (ALA). The subsequent three steps that follow are common to the biosynthesis of all tetrapyrroles. After the formation of uroporphyrinogen III, the pathways for vitamin B12, coenzyme F430, heme d1, and siroheme formation branch off from the pathway, leading to the formation of other tetrapyrrole compounds of biological importance (e.g., heme and chlorophyll).

In the presence of pyridoxal phosphate, ALA synthase (ALAS) catalyzes the condensation of succinyl-CoA and glycine with the elimination of CO2 in the production of ALA. ALAS has two different isoforms coded by separate genes: ALAS2 gene is an erythroid-specific isozyme located on chromosome X, whereas ALAS1 is a ubiquitous housekeeping enzyme coded by a gene on chromosome 3.

Each ALAS gene is under different regulatory control mechanisms. Indeed, ALAS2 is induced only during active heme synthesis, where the rate is limited by the availability of iron and is not inhibited by heme. In contrast, ALAS1 is the rate-limiting enzyme in hepatic heme production and is controlled by the uncommitted regulatory heme pool. Indeed, heme stimulates the degradation of the ALA synthase mRNA and may play a role in the down regulation of ALA-synthase gene transcript production itself. In addition, heme inhibits the uptake of a precursor ALA synthase into the mitochondria and, as recently shown in our laboratory, is also capable of decreasing stability of the ALAS1 protein in the mitochondria. Finally, heme-oxygenase 1 (HMOX1) may indirectly exert control on the regulatory hepatic heme pool by catalyzing heme degradation. Thus, the level of heme in hepatocytes plays a critical role in regulating levels of ALAS I and the flux of intermediates in the pathway.

Once formed, ALA exits the mitochondria. In the cytoplasm, two molecules of ALA are condensed by ALA dehydratase/porphobilinogen synthase (ALAD/PBGS) to produce porphobilinogen (PBG), a monopyrrole. PBG deaminase/hydroxymethylbilane synthase (PBGD/HMBS) then polymerizes four molecules of PBG to form hydroxymethylbilane/preuroporphyrinogen, a linear tetrapyrrole. The latter compound readily cyclizes nonenzymatically to form uroporphyrinogen I. However, in the presence of normal activity of uroporphyrinogen III (co)-synthase, hydroxymethylbilane is converted to uroporphyrinogen III. Stepwise decarboxylation of uroporphyrinogen I or III then occurs by the action of uroporphyrinogen decarboxylase (UROD) to form coproporphyrinogen I or III. Coproporphyrinogen III is transported to the mitochondria, where coproporphyrinogen oxidase (CPOX) catalyzes the production of protoporphyrinogen IX. Protoporphyrinogen oxidase (PPOX) then catalyzes a dehydrogenation reaction that leads to the formation of protoporphyrin IX. In the final step of heme biosynthesis, ferrochelatase (FECH) catalyzes the insertion of ferrous iron into the protoporphyrin ring to form the final product, heme (Figure 1).

Acute porphyria primer

ALA dehydratase porphyria (ADP)

ADP is a very rare form of acute porphyria characterized by massive overprodcution of ALA with minimal elevations of PBG. Because of the high level of activity of ALAD normally present (relative to the much lower levels of ALAS or PBGD), severe (>95%) deficiencies of ALAD, due to mutations in both alleles, are required for signs and symptoms to occur. Only six cases have been reported in Europe and the United States. Although phenotypic expression is rare, the frequency of heterozygotes (with 50% of normal ALAD activity) in the population can be as high as 2%. These heterozygotes may have a higher likelihood of developing biochemical and clinical manifestations if exposed to environmental toxins, such as lead, that inhibit ALAD.

ALAD is an octamer that catalyzes the formation of PBG by the condensation of two molecules of ALA. To accomplish this, it requires a divalent zinc cation and an intact sulfhydryl group per subunit. Lead potently inhibits ALAD activity by displacement of zinc from the enzyme. In lead poisoning, urinary ALA and coproporphyrin may be markedly increased and neurological symptoms resembling acute porphyric attacks may occur. The biochemical and clinical features it shares with lead poisoning have led some to use the term "plumboporphyria" to describe ADP. Similarly, hereditary tyrosinemia type I may lead to acute porphyric-like symptoms via the production of succinylacetone (4,6-dioxoheptanoic acid), a potent inhibitor of ALAD. Hence, it is important to rule out these two conditions before making a diagnosis of ADP.

Due to the sequential nature of heme biosynthesis, ALAD deficiency leads to 10 to 20 times elevated ALA levels compared to that of PBG. On the other hand, the same sequential nature and higher activity of ALAD in comparison to ALAS lead to greater amount of urinary PBG than ALA in AIP. The identical clinical manifestations of AIP and ADP along with the porphyric symptoms in lead poisoning and hereditary tyrosinemia type I, suggests that ALA or its metabolite(s) is the neurotoxic agent that underlies acute porphyrias. Indeed, elevated urinary ALA is the common biochemical marker found in all of the four acute porphyrias and in symptomatic lead poisoning and hereditary tyrosinemia type I.

Acute intermittent porphyria (AIP)

AIP is the most common and most severe form of the acute hepatic porphyrias. It is widespread in the Northern European countries of Scandinavia, Sweden, Britain, and Ireland, with an estimated prevalence of 60 to100 per 100,000. In the United States, its prevalence is lower and thought to be around 5 to 10 per 100,000. It is an autosomal dominant disorder that results from the half-normal activity of hepatic PBGD/HMBS that is consistent with a heterozygous state. The two isozymes (ubiquitous and erythroid) of the protein arise from the alternative splicing of an identical gene transcript, with the latter missing exon 2. Thus, the erythroid-specific PBGD is composed of 344 amino acid residues, whereas there are 361 in the ubiquitous isoform.

More than 200 mutations of the HMBS gene associated with AIP have been reported and have been divided into at least three groups. Type I is a cross-reactive immunological material (CRIM)-negative form in which HMBS activity is decreased by at least 50% in all tissues. Type II comprises ~5% of AIP, and is due to mutations in exon 2 of the ubiquitous transcript. Thus, the decreased activity is found only in nonerythroid cells. Type III is a CRIM-positive subgroup in which the genetic defect is found in all tissues. The occurrence of type II explains why only ~95% of AIP subjects have decreased erythrocyte PBGD activity. Although biochemically distinct, the clinical importance of these subgroups is still unclear.

Similar to ADP, the genetic defect that leads to AIP occurs prior to porphyrin synthesis. Yet just as in ADP, biochemically active AIP also presents with an elevation of certain urinary porphyrins, namely, uroporphyrin and coproporphyrin. This is partially explained by nonenzymatic conversion of PBG to uroporphyrin. The urinary PBG level in AIP is higher than that of ALA. This pattern is sufficiently characteristic such that if it is not seen, a diagnosis other than AIP is more likely.

Hereditary coproporphyria (HCP)

Similar to most of the acute porphyrias, HCP is an autosomal dominant hepatic porphyria with variable penetrance. It is less frequent than both AIP and VP and results from at least 50% deficiency of coproporphyrinogen oxidase (CPOX) activity. It is characterized by a 10- to 200-fold increase in urinary and fecal coproporphyrin III, compared with controls. The CPOX gene has been mapped to chromosome 3q12 and is about 14 kb in length. Its expression is regulated in a tissue-specific manner. HCP is known to be associated with a number of mutations with variable phenotypes. The most frequent of these is due to the substitution of lysine residue by glutamic acid (K304E). This mutation leads to increased fecal harderoporphyrin (tricarboxylate porphyrin) and coproporphyrin, hence, was aptly named harderoporphyria.

Like VP, HCP also presents with elevated urinary ALA and PBG due to the ability of the accumulated intermediates to inhibit PBGD. More specifically, coproporphyrinogen III has been shown to decrease the Vmax of PBGD. In HCP, urinary ALA levels exceed that of PBG and usually normalize between attacks, in contrast to the pattern observed in AIP. Although it is generally thought that the neurovisceral manifestations of HCP are milder than those of AIP, fatalities from respiratory paralysis have been reported. Furthermore, around 30% of cases may present with cutaneous vesiculobullous eruption resembling the lesions of VP and PCT.

Variegate porphyria (VP)

VP has also been called the "royal" malady (due to its possible connection with European aristocracy), protocoproporphyria, neurocutaneous porphyria, and South African porphyria. It is an autosomal dominant disorder of low penetrance that arises from 50% decrease in protoporphyrinogen oxidase activity (PPOX) and is highly prevalent in Afrikaners of South Africa. This is due to a founder effect and can be traced to a couple from the Netherlands who emigrated and married in 1688 in what is now South Africa. It is estimated that as many as 20,000 South Africans carry a single mutation (R59W) that leads to VP. For this reason, VP is the most common acute porphyria in South Africa in comparison to other countries where AIP is the predominant form.

It was first reported in 1945 that the gene that encodes the human PPOX is located on chromosome 1q22-23. Since its discovery, many different mutations have been documented.

Patients present with the neurovisceral symptoms common to all acute porphyrias but may also present with cutaneous symptoms similar to PCT. During acute attacks, VP is characterized by increased fecal protoporphyrin and coproporphyrin. In addition, there are increased levels of urinary ALA, PBG, and coproporphyrin III. Owing to the ability of protoporphyrinogen IX to inhibit PBGD, ALA, and PBG levels may increase further during acute attacks, unlike those seen in chronic cutaneous porphyrias.

Usual signs and symptoms of acute porphyria

A prodrome consisting of minor behavioral changes usually precedes an acute episode and includes anxiety, restlessness, or insomnia. For most sufferers, this is followed by major neurologic manifestations of acute porphyrias that include abdominal pain, peripheral neuropathy, and psychiatric disturbances. In addition, gastrointestinal complaints, various neuropathies, and psychiatric disturbances are also observed. More specifically, nausea, vomiting, and constipation are common. Cardiovascular manifestations due to sympathetic overactivity or autonomic neuropathy include tachycardia and systemic arterial hypertension.

Initial attacks usually occur in the early third decade of life and can be fatal. Porphyric episodes may be exacerbated by drugs such as sulfonamides, phenobarbital, or phenytoin, which, sometimes, have been administered inadvisedly to treat manifestations of the disease (e.g., seizures); hence, early diagnosis of carriers and affected individuals is important. Fortunately, approximately 80% of carriers of mutant genes that underlie AIP, VP, and HCP remain asymptomatic throughout their lives. For the remaining 20% who present with symptoms, one or few attacks with full recovery are the norm. Fortunately, fewer than 10% of all those with genetic defects develop recurrent acute attacks. (See Table II for a listing of presenting signs and symptoms of acute porphyric attacks.)

Table II. Presenting signs and symptoms of acute porphyric attacks

Signs and symptoms

Approximate frequency, % (as reported in case series)

Comments

Gastrointestinal

Abdominal pain

85-95

Usually colicky (cramping) and unremitting (for hours or longer), mainly lower abdominal. Not accompanied by peritoneal signs, fever, or leukocytosis.

Vomiting

43-88

Nausea and vomiting often accompany abdominal pain.

Constipation

48-84

May be accompanied by bladder paresis.

Diarrhea

5-12

Neurologic

Pain in extremities, back, chest, or head

50-70

Pain may begin in the chest or back and move to the abdomen. Extremity pain indicates involvement of sensory nerves, with objective sensory loss reported in 10-40% of cases.

Paresis

42-68

May occur early or late during a severe attack. Muscle weakness usually begins proximally rather than distally and more often in the upper rather than lower extremities.

Respiratory paralysis

9-20

Preceded by progressive peripheral motor neuropathy and paresis.

Mental symptoms

40-58

May range from minor behavioral changes to agitation, confusion, hallucinations, and depression.

May require treatment during acute attacks, and sometimes becomes chronic.

Usual constellation of clinical features of acute porphyria

Acute porphyrias should be considered in any patient with the prominent GI, neurologic, and cardiovascular symptoms described, especially after puberty. With the exception of possible cutaneous manifestations of VP and HCP, the four acute porphyrias are otherwise clinically indistinguishable during attacks. Abdominal pain of unknown etiology, particularly after an expensive, time consuming, and unproductive search should be seriously considered for workup. If nonspecific symptoms remain undiagnosed, unnecessary surgery is sometimes performed, exposing the patient to risks without any conceivable benefit.

Pathophysiology of acute porphyria

In all forms of acute porphyrias, it is believed that up-regulation of ALAS1 with marked ALA accumulation lead to the neurologic signs and symptoms observed. Indeed, some investigators have noted that increased ALA levels in the brain may inhibit release of gamma-aminobutyric acid and/or binding to its receptors. There are at least three known causes of ALAS1 over expression. First, certain porphyrinogenic lipophilic compounds interact with nuclear receptors, which, in turn, increase activation of drug-response elements in the upstream enhancer region of ALAS1. Second, a deficiency of glucose or other gluconeogenic compounds leads to induction of HMOX1 and up-regulation of peroxisome proliferator-activated receptor-gamma-coactivator 1-alpha (PGC 1-alpha), which increases ALAS1 gene transcription. Third, intracellular heme deficiency leads to increased stability of ALAS1 mRNA, relief of transcriptional heme-inhibition of ALAS1 gene, and reduced inhibition of ALAS translocation into the mitochondria. In addition, most drugs that exacerbate acute porphyrias decrease the regulatory heme pool in hepatocytes either by inducing cytochrome p-450 or by acting as suicide substrates for the heme of cytochrome p-450. These include various compounds, such as the polycyclic aromatic hydrocarbons seen in tobacco smoke, ethanol, and medications as common as barbiturates, sulfonamides, and hydantoins.

Female sex steroids, especially progesterone, have also been found to induce ALAS1. In fact, many women suffer mid-cycle attacks due to the increase of heme catabolism and up-regulation of ALAS1 induced by progesterone. This at least partially explains why attacks are more common in women during the luteal phase of the menstrual cycle and during pregnancy and are rare before puberty and after menopause.

A tabular or chart listing of features and signs and symptoms

Are there pathognomonic or characteristic features in acute porphyria?

No universal sign or symptom is pathognomonic of porphyria, and at least 5% to 10% of acute sufferers may not have the most common features, such as abdominal pain and tachycardia. Furthermore, family history may be unrevealing due to variable clinical expression or to de novo mutations. A constellation of symptoms in the proper clinical scenario is thus the best guide pointing to initial suspicion of acute porphyria. Young women with histories of severe, recurrent episodes of abdominal pain without evidence of peritoneal signs or acute infection should be assessed for acute porphyria. Other useful clues are a history of dark urine, especially reddish urine, tachycardia, and systemic arterial hypertension during attacks.

Less common clinical presentations of acute porphyria

Although cardiovascular complications are rarely severe, acute attacks can be accompanied by severe adrenergic crises that lead to hypertensive emergencies causing encephalopathy, seizures, and stroke. Other neurologic manifestations may be secondary to acute ischemia of the brain ascribed to reversible vasospasm. In a few cases, acute attacks of AIP have been documented to cause sudden death, presumably due to cardiac arrhythmias. The mortality of acute attacks that went unrecognized is estimated at 5% to 10%. Furthermore, severe sensory neuropathy may cause severe pain and stiffness, while motor neuropathy can also cause paralysis of the diaphragm intercostal muscles, which may lead to respiratory distress requiring artificial ventilation in some patients. More ominous is the respiratory failure secondary to bulbar paralysis, which is likely due to delay in diagnosis. Finally, electrolyte abnormalities may also complicate porphyric attacks. Indeed, hyponatremia is common enough in acute attacks that its presence may help support suspicion of underlying porphyria.

Other diseases and conditions that might mimic signs, symptoms, or clinical features of acute porphyria

Most elevations of urinary and or fecal porphyrins are not due to porphyria but rather due to a variety of other conditions, such as liver disorders, bone marrow disorders, drugs, or alcohol. These fall under the broad designation: "secondary porphyrinurias." Furthermore, iron deficiency anemia, lead toxicity, and increased erythropoiesis lead to increased erythrocyte zinc protoporphyrin, which may be reported erroneously by some reference laboratories as "free protoporphyrin." Fecal porphyrins may be elevated in patients whose diet is rich in meat or in those with gastrointestinal bleeding.

The various causes of secondary porphyrinurias may be mistaken for any type of porphyria (whether acute or chronic-cutaneous) when a misinterpretation of a mildly elevated porphyrin assay is accompanied by a rather convincing clinical scenario. Rarely, chemical exposures may blur the boundary between secondary porphyrinuria and a legitimate porphyric attack. Indeed, certain chemicals (e.g., carbamazepine, hexachlorobenzene, sedormid) may cause marked elevation of porphyrins and their precursors, accompanied by cutaneous or neurovisceral manifestations.

Fortunately, the majority of porphyrinogenic substances produce, at most, mild elevations in porphyrin levels (usually and mainly coproporphyrin) and are not associated with clinical features. More important, porphyrins do not cause neurological manifestations and only high levels of ALA (as is seen in lead toxicity and hereditary tyrosinemia type I), have been suggested to be neurotoxic.

Indeed, with the exception of lead poisoning, secondary porphyrinurias are not associated with substantial elevation of urinary ALA or PBG excretion. In such cases, other causes explaining the observed neurological manifestations that may have both direct neurotoxic and porphyrinuric effects, such as alcohol or inflammation, should be sought. Thus, remembering that elevated urinary excretions of PBG and/or ALA is the sine qua non of a true symptomatic acute porphyric attack avoids this common pitfall. Other useful clues suggestive of secondary porphyrinuria include urinary porphyrins that are less than 3-fold above the upper limit of normal, mainly due to coproporphyrins; normal or minimal increased fecal porphyrins, which helps exclude HCP and VP; absence of elevated urinary PBG early in remission; and lack of correlation between symptoms and porphyrin levels on repeat measurement (Table III).

During the late 1990s, the diagnosis of multiple chemical sensitivity syndrome (MCSS) was in vogue and was used to describe persons with multiple subjective symptoms attributed to chemical exposures. It was suggested by some to be a manifestation of a mild form of true acquired porphyria due to modest increases of urinary coproporphyrin excretion and decreased erythrocytic coproporphyrinogen oxidase. However, since its inception, MCSS has not been recognized by the American Medical Association as a clinical syndrome and has been shown to have biochemical patterns incompatible with those of any inherited porphyrias. Furthermore, its purported association with HCP has been shown to have been based on flawed laboratory paradigm. Much the same way as previously diagnosed patients with MCSS showed similarities with somatization disorders, the psychiatric manifestations of acute porphyria may also be confused with various psychiatric disorders (especially when combined with an isolated secondary porphyrinuria).

Common pitfalls in the diagnosis of porphyria

Unfortunately, misdiagnoses of porphyrias are common and are likely either due to poor laboratory technique or inappropriate workup in combination with clinical inexperience. It is essential that laboratory data for the diagnosis be reviewed carefully, no matter how convincing the clinical picture. It is therefore equally important that biochemical analysis of urine, plasma, serum, whole blood, and fecal samples be sent to an experienced laboratory, especially equipped to analyze porphyrins.

We recommend sending these samples to the Porphyria Laboratory at University of Texas Medical Branch, headed by Dr. Karl Anderson, at 700 Harborside Drive, Ewing Hall 3.102, Galveston, Texas 77555-1109. A list of other laboratories equipped in biochemical testing of porphyrins and overseen by a porphyria expert follows:

For patients with documented biochemically active porphyria, we recommend that genetic tests be done at the Department of Genetics and Genomic Sciences at Mount Sinai School of Medicine, headed by Dr. Robert. Desnick. Samples should be sent to 1 Gustave L. Levy Place, Box 1498, New York, N.Y. 10029.

How can I confirm the diagnosis?

Detection of elevated urinary PBG (not porphyrins) excretion is both sensitive and specific and is the cornerstone of diagnosis in an acute attack. Elevated urinary PBG is substantially increased in AIP, HCP, and VP and is not significantly increased in other conditions. ALA, not PBG, is increased in lead poisoning.

A substantial increase of PBG levels of more than10 times the upper limit is strongly suggestive of one of the three common acute porphyrias (AIP, HCP, and VP) and should be documented before treatment (with hematin) is initiated. Indeed, excretion of urinary PBG is usually increased by more than 20-fold during an acute attack. Older qualitative methods for PBG detection, such as the Watson-Schwartz and Hoesch tests, are now rarely performed. Instead, a kit (Trace-PBG®) based on the standard Mauzerall-Granick method that utilizes an anion exchange resin is preferred and should be made available in all major medical facilities. The kit uses a color chart that provides an estimate of PBG levels. Regardless of the initial results of this test, however, the same spot urine should be sent for quantitative determination of ALA, PBG, porphyrins, and creatinine. In effect, this second-line test confirms the qualitative results of Trace-PBG® and will also detect patients with ADP, lead poisoning, or hereditary tyrosinemia type I. (See Table IV for first- and second-line laboratory tests for acute porphyrias.)

Table IV. First-line laboratory tests for porphyrias screening and second-line tests for further evaluation when initial test result is positive

Testing

Acute neurovisceral symptoms

Cutaneous photosensitivity

First-line

Urinary ALA, PBG, and total porphyrins (quantitative; random urine)3

Total plasma porphyrins1,2

Second-line

Urinary ALA, PBG, and total porphyrins3 (quantitative; 24-hour urine)

Erythrocyte porphyrins

Urinary ALA, PBG, and total porphyrins3 (quantitative, 24-hour urine)

Total fecal porphyrins3

Total fecal porphyrins3

Erythrocyte PBGD

Total plasma porphyrins1

Samples for second-line testing should be sent to experienced laboratories to avoid false negative results. If substantial elevations of spot urinary PBG and/or ALA levels are detected, further second-line testing is warranted. This includes measurement of erythrocyte PBGD levels, spot total fecal, and total plasma porphyrins. Urinary porphyrins should have been sent as part of the initial workup and interpreted along with other second-line tests. Together, these tests establish a biochemical profile that identify a specific porphyria or, in rare cases, the presence of two enzymatic deficiencies in a single individual (dual porphyria).

The systematic approach outlined ensures proper diagnosis, treatment, and avoidance of unnecessary grief of misdiagnosis, but it also curtails the expense of subsequent enzymatic assays and genetic analysis. Once properly diagnosed, the patient should be advised to indefinitely retain copies of key laboratory data and consultation notes to avoid further confusion, delay, and expense in possible subsequent attacks.

What tests are useful if the diagnosis is still in doubt?

In most instances, the biochemical profiles established by measuring porphyrins and their precursors are sufficient to make a diagnosis of porphyria. (See Figure 2 for a diagnostic algorithm.) DNA testing is useful in the index patient when the clinical suspicion remains high during prolonged periods of remission. However, once biochemical profiles establish the type of porphyria via the recommended second-line tests, DNA studies and enzyme activity measurements are recommended to help confirm the type of acute porphyria (Table V). Furthermore, they allow identification of asymptomatic relatives so that appropriate genetic counseling can be provided. Lists of updated mutations are available via the human gene mutation database (http://www.hgmd.cf.ac.uk/ac/index/php). Cytosolic enzymes of heme biosynthesis (ALAD, PBGD, UROS, and UROD) can be measured in RBCs. Unfortunately, heme pathway mitochondrial enzymatic assays including FECH, PPOX, and CPOX are not available in North America. Thus, lack of cost-effectiveness is likely part of the reason why the enzymatic assays that underlie HCP, VP, and EPP are not included in the recommended routine second-line tests in the United States.

What other diseases, conditions, or complications should I look for in patients with acute porphyrias?

Aside from the acute manifestations described, some patients develop chronic signs and symptoms that may reflect previous unresolved neurologic damage. Indeed, some patients experience chronic neuropathic pain, which may also contribute to the increased risk of depression and suicide (Table II). Other long-term complications include chronic arterial hypertension and subsequent renal impairment. Patients may also develop chronic liver damage, hepatic fibrosis, cirrhosis, and are at markedly increased risk of developing hepatocellular carcinoma. Despite these risks, however, progressive liver disease is not characteristic of acute porphyrias.

What is the right therapy for the patient with acute porphyrias?

Treatment is based on reversal of ALAS1 inductions and is accomplished by either providing glucose or replenishment of the regulatory heme pool, or both. A high glucose state with adequate insulin (which may have to be administered if there is diabetes mellitus) prevents the up-regulation of PGC 1-alpha and down-regulates the ALAS1 gene. Most authorities recommend a glucose intake of at least 300g per day. Because of nausea, vomiting, and poor gastrointestinal motility, glucose is usually given intravenously as 3L of 10% glucose solution daily.

Intravenous heme therapy should also be used for all but the mild attacks. IV heme is available either as a lyophilized hydroxyheme (hematin, Panhematin®) or as a heme arginate solution (Normosang®). Normosang®, manufactured by Orphan Europe, is available in the EU and South Africa. Panhematin®, on the other hand, is manufactured by Lundbeck and is the only form of IV hemin therapy available in the U.S.A. Both forms of IV hemin therapy have been shown to be safe in pregnancy.

Normosang® is available as a concentrated stock solution that requires dilution with normal saline (NS) immediately before use. The working solution is then infused at a dose of 3 to 4 mg/kg over 20 minutes daily for 4 consecutive days. The infusion site is then flushed thoroughly with NS to reduce the risk of thrombophlebitis If thrombophlebitis develops, 5% human serum albumin may be included in the diluents along with NS.

A stable hematin solution is prepared by reconstitution of a 313-mg vial of Panhematin® with 132 mL of 25% human serum albumin solution. Once gently swirled, a 2.4 mg/mL concentration of hemin results as a heme-albumin, which is then used to calculate the volume needed to deliver a dose of 3 to 4 mg/kg per day. The required volume is then infused by piggy back to an IV line that is infusing NS at a moderate rate to a large peripheral vein. The full dose should be infused over at least 1 hour or at a rate that should not exceed 1 mL/min. After the calculated dose has been infused, NS should be continued for about 10 minutes to clear the line and vein of the mixture.

Alternatively, peripherally inserted central catheter, central line, or a central port with the appropriate terminal NS flush may be used if available. It is currently recommended that these steps (above) be repeated daily for at least 4 days. Extended treatment beyond 4 days is indicated if recovery is not evident beyond this time, especially in patients with advanced neuropathy.

Supportive and symptomatic treatment is paramount (Table VI). The patient should be monitored in an intensive care unit and preferably under the care of or consultation with a porphyria expert. Daily monitoring to ensure control of urinary porphyrin excretion during treatment is also ideal. However, urinary porphyrin precursors (e.g., ALA and PBG) may increase rapidly once hemin infusion is discontinued. Fortunately, this increase is usually not accompanied by symptoms.

Table VI. Supportive and symptomatic treatment of acute porphyrias

Scenarios/symptoms

Treatment

Definitive treatment of any acute attack:

1. Identification and removal of known precipitants. Removal of unnecessary undocumented medications or possible precipitants.2. ICU monitoring and preferably consultation with a porphyria expert.3. Symptomatic treatment, e.g., correction of electrolyte abnormalities, control of tachycardia, control of hypertension, etc.4. Either or both (depending on the clinical scenario): a. Carbohydrate loading PO or IV at a minimum of 300-500g/day. If to be given IV, infuse 3L of 10% glucose solution over 24 hours. b. IV hemin therapy (Panhematin® if in the U.S; Normosang® only available in EU and South Africa) at a dose of 3-4 mg/kg body weight per day for at least 4 days. 5. Daily monitoring of urinary porphyrin excretion during IV therapy has been suggested by some authors; however, it is not needed routinely.

1. Early physiotherapy2. Monitor closely for any signs of respiratory failure.

Respiratory failure

Mechanical ventilation; intubation

Dysphagia

NGT/Feeding tube placement

Bladder paresis

Urethral catheter should be inserted. Topical Xylocaine is safe to use.

Constipation

Sorbitol, senna, or lactulose is safe.

Bowel paresis (ileus)

Neostigmine can be administered.

Diarrhea

Loperamide may be administered.

Opiates are usually required for pain and phenothiazines for nausea, vomiting, anxiety, and restlessness. Adequate fluid resuscitation is essential, especially when treating tachycardia and systemic arterial hypertension with beta-blockers. Chloral hydrate may be used for insomnia. Correction of electrolyte abnormalities, (e.g., hyponatremia and hypomagnesemia) is especially important in attacks involving seizures. Seizures are difficult to treat because most anti-seizure drugs can exacerbate acute porphyria. However, benzodiazepines are probably safe in low doses, along with vigabatrin and gabapentin. Lists of safe and unsafe drugs in porphyria can be found at http://www.drugs-porphyria.org for the EU, South Africa, and Canada, and at http://www.porphyriafoundation.com for the United States.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

If an attack occurs despite avoidance or inadvertent exposure to known triggers, then either glucose loading alone or glucose with IV hemin therapy is appropriate, depending on the severity of attack. Clinical improvement is usually rapid and usually occurs within 1 to 2 days of starting hemin therapy. It is recommended that patients receive at least a 4-day treatment course of IV hemin. Longer courses of daily IV hemin may be considered, depending upon clinical response.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Treatment with large volumes of IV glucose may result in exacerbation of hyponatremia of an acute attack. Heme is preferred because it has manifold effects to decrease ALAS1. Immediate side effects of hemin therapy include phlebitis at infusion site and transient anticoagulant effect. Phlebitis may at times be severe and can compromise venous access with repeated dosing. Hemin reconstitution with albumin decreases the likelihood of these complications and may enhance therapeutic efficacy. Other uncommon side effects reported include fever, malaise, aches, hemolysis, one reported case of transient renal failure after a 12-mg/kg dose, and a case of transient circulatory collapse.

Other treatment modalities are considered on a case-by-case basis. For example, nasal or subcutaneous long-acting LHRH agonist may be used in women who have frequent cyclical attacks during their luteal phases. Treatment should begin within 2 days after the onset of menstruation. Buserelin nasal spray at 0.9 to 1.2 mg/day may be administered as 0.15 mg in each nostril, TID-QID. Alternatively, Triptorelin depot at a dose of 3.75 mg SQ every month can be administered to achieve and maintain medically induced menopause. Among women receiving LHRH agonists for more than 3 months, bone mineral density should be assessed for osteoporosis and calcium (1-2 g PO daily) and bisphosphonates added when indicated.

Liver transplantation may be considered for very rare cases of homozygous AIP, VP, and HCP or those with the severest forms of these disorders or the hepatopathy that may occur in EPP. Patients with acute porphyria undergoing liver transplant face the same complications as any transplant patients. Combined liver-kidney transplantation may also be considered in patients with severe chronic symptoms of acute porphyria and end-stage renal disease. Potential complications of transplantation and immunosuppression should be weighed carefully against possible benefits. Hepatocyte transplantation and gene therapy are possible future therapies. (See Table VII for therapies and management practices for varying scenarios of acute porphyria.)

1. Identification and elimination of known triggers.2. ICU monitoring and, preferably, a referral to a porphyria expert.3. Symptomatic treatment, e.g., correction of electrolyte abnormalities, control of tachycardia, control of hypertension, etc.4. Intravenous glucose therapy for mild attacks and in combination with IV hemin therapy in moderate to severe attacks.5. Daily monitoring of urinary porphyrin excretion during IV therapy has been suggested by some authors; however, it is not needed routinely. Need to document biochemical response every 3 days is perhaps often enough.

1. Careful history to identify known and possible precipitants.2. Referral to a nutritionist to initiate a well-balanced, nutritionally adequate diet with at least 300 g of carbohydrates per day.3. Depending on history and physical exam, consider LHRH agonist, liver transplant, or combined liver-kidney transplant. Future therapy may possibly include enzyme replacement, gene therapy, and hepatocyte transplantation.

Listing of these, including any guidelines for monitoring side effects.

How should I monitor the patient with acute porphyrias?

Once diagnosed, the patient should be educated about the disease and the availability of other resources that help identify and avoid triggers of another attack. General information about the disease as well as important advice is easily accessible at the American Porphyria Foundation website at http://www.porphyriafoundation.com/.

The patient should also be advised to avoid alcohol, smoking, and drugs and to maintain adequate nutrition. As in any condition that requires special attention, patients are encouraged to wear medical alert bracelets and wallet cards to guide medical personnel regarding appropriate therapy. Patients who present with frequent attacks even after removal of precipitating factors could be evaluated by a nutritionist and follow a well-balanced diet. Depending on the pattern and clinical scenario of a confirmed attack, various therapeutic modalities previously mentioned can be employed.

Patients with acute porphyrias are also at increased risk of developing end-stage renal disease, which partly may be a result of chronic systemic arterial hypertension. Thus, careful monitoring and control of blood pressure may substantially delay full-blown renal failure. Patients are also prone to develop hepatocellular carcinoma and therefore require monitoring of alpha-fetoprotein levels, as well as need hepatic imaging, although it is not clear how often these should be done in patients with porphyria without cirrhosis. Finally, psychiatric symptoms, most especially depression and risk for suicide, are important to recognize in patients with frequent attacks or chronic symptoms. For such patients, pain management and early psychiatric referral is paramount.

What's the evidence?

(The authors are all experts in the field of porphyria. They met to address concerns about delay in diagnosis, misdiagnosis, and inappropriate therapy in acute porphyrias. The article addresses the major pitfalls and misconceptions in diagnosing acute porphyria. The authors also emphasized key clinical features of an acute attack and complications that need to be immediately addressed. The article further emphasizes a rational algorithm in the diagnosis of acute porphyrias. Work on this article led to the development of U.S. consortium for the study of porphyrias).

(The author is a renowned expert in porphyria. The article provides a brief description of heme biosynthesis and the pathophysiology that underlie an acute attack. It highlights the common clinical manifestations and complications of the condition and provides a brief recommendation for diagnosis and treatment of acute porphyrias.)

(The author is a renowned expert in porphyria. The article provides a brief description of the prototypic porphyrias and proceeds to discuss each type in some detail. The article further stresses a simplified algorithm in the diagnosis of both acute and cutaneous porphyrias.)

(The authors examine the available chemical and fluorometric methods in the diagnosis of porphyria. The article also provides useful tables that outline the different biochemical and fluorometric patterns of individual porphyria. Special emphasis is also given to molecular approaches to the diagnosis of porphyrias. Differential diagnosis and common misconceptions about porphyrias are discussed.)

(The authors provide a thorough review of the hepatic porphyrias. The article emphasizes the physiology and biochemistry of porphyrin and heme, classification of the different porphyrias, as well as the pathophysiology underlying both cutaneous and acute manifestations of the disorder. It provides a list of drugs that may trigger an acute attack and those that may be safely administered in patients afflicted with porphyria.)

(The authors are based at the University of Milan and provide a brief, yet thorough, summary of porphyrias. It provides useful tables showing the different clinical manifestations of acute porphyrias, biochemical profiles of the different types of porphyrias, and the genetic mutations that underlie each individual porphyria.)

(The authors are known experts in porphyria. The article provides a thorough background regarding the topic, with emphasis on the pathophysiology and genetics of the condition. It provides advice on the diagnosis and treatment of porphyria.)

(The authors provide a brief description of acute porphyria, PCT, and EPP. In a simple list format, the authors suggest the treatment options for each common complication of porphyria.)

Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010;375:924-37.

(The authors are based in France and are known experts in the field of porphyria. Their laboratory is part of the European Porphyria Network (EPNET), the counterpart of the American Porphyria Consortium. The article highlights the clinical manifestations of both acute and cutaneous porphyria, and provides helpful illustrations to better understand the disease. The authors also discuss the rare recessive porphyrias along with the complicated genetics of EPP.)